Alghamdi Alaa, Thakar Charuhas V, Amlal Hassane
Department of Pharmacology and Systems Physiology, College of Medicine, University of Cincinnati, Cincinnati, OH, 45267, USA.
Department of Pharmacology, College of Clinical Pharmacy, Imam Abdulrahman Ben Faisal University, Dammam, Saudi Arabia.
Purinergic Signal. 2025 Aug 12. doi: 10.1007/s11302-025-10105-7.
We have previously reported that adenine at high doses interferes with the vasopressin signaling pathway, causes massive diuresis and volume depletion, and ultimately leads to renal failure. In the present study, we examined the effects of adenine on renal salt and water handling in a time course and dose-response study in rats housed in metabolic cages and fed control or adenine-containing diet at 1500, 2000, 2500 mg/kg and euthanized after 1, 3, and 7 weeks. Adenine at 2000 and 2500 mg/kg caused early and significant polyuria, polydipsia, and decreased urine osmolality in a dose-dependent manner without significantly affecting food intake, blood volume, blood electrolyte levels, or acid-base composition. The impaired water balance resulted from the downregulation of apical water channel AQP2 in the outer and inner medulla but not in the cortex. Adenine did not alter electrolytes (Na, K, Cl) excretion at these doses for up to 3 weeks. However, a slight but significant increase in salt excretion was observed in adenine-fed rats for 7 weeks, which correlates with a significant downregulation of NKCC2, mostly in rats fed 2500 mg/kg adenine. Adenine-fed rats exhibited a substantial resistance to vasopressin in response to water deprivation or vasopressin treatment. Lastly, 2500 mg/kg adenine prevented the development of hyponatremia in a rat experimental model of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). In conclusion, adenine acts as an aquaretic agent in the kidney at lower doses and during a short feeding period. It can be used as a vasopressin antagonist in conditions associated with hyponatremia.
我们之前曾报道，高剂量腺嘌呤会干扰血管加压素信号通路，导致大量利尿和容量耗竭，最终引发肾衰竭。在本研究中，我们在一项时间进程和剂量反应研究中，对饲养在代谢笼中、喂食对照饮食或含1500、2000、2500 mg/kg腺嘌呤饮食的大鼠进行了研究，并在1、3和7周后实施安乐死，以检测腺嘌呤对肾脏盐和水代谢的影响。2000和2500 mg/kg的腺嘌呤以剂量依赖性方式导致早期且显著的多尿、烦渴和尿渗透压降低，而对食物摄入量、血容量、血液电解质水平或酸碱组成无显著影响。水平衡受损是由于外髓和内髓而非皮质中的顶端水通道蛋白2（AQP2）下调所致。在这些剂量下，腺嘌呤在长达3周的时间内未改变电解质（钠、钾、氯）排泄。然而，在喂食腺嘌呤7周的大鼠中观察到盐排泄略有但显著增加，这与钠钾氯协同转运蛋白2（NKCC2）的显著下调相关，主要发生在喂食2500 mg/kg腺嘌呤的大鼠中。喂食腺嘌呤的大鼠在缺水或血管加压素治疗时对血管加压素表现出显著抗性。最后，2500 mg/kg腺嘌呤在抗利尿激素分泌不当综合征（SIADH）大鼠实验模型中预防了低钠血症的发生。总之，腺嘌呤在较低剂量和短时间喂食期间在肾脏中起利水剂作用。在与低钠血症相关的情况下，它可作为血管加压素拮抗剂使用。
